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Macrophages play crucial roles in regulating both homeostatic and inflammatory responses, with classical activated (M1) and alternatively activated (M2) subsets defined by the surrounding micro-environment. Renal fibrosis, developed from persistent inflammation, is worsened by M2 macrophages, yet the precise mechanisms underlying macrophage M2 polarization remain unclear. In this study, we investigated the role of Kv1.3, one of the primary potassium channels which is expressed in both innate and adaptive immunity, on macrophage M2 polarization and renal fibrosis. Our findings demonstrated that genetic or pharmacological inhibition of Kv1.3 significantly suppressed the expression of M2 markers and STAT6 phosphorylation. Furthermore, pharmacological inhibition of Kv1.3 by PAP-1 attenuated renal inflammation and fibrosis with decreased infiltration of macrophage infiltration and M2 polarization by employing the unilateral ureteral obstruction (UUO) renal fibrosis model. Mechanistically, we revealed that Kv1.3 was required for STAT6 phosphorylation in a mitochondria membrane potential dependent manner. Collectively, this study suggests that Kv1.3 is essential for macrophage M2 polarization and highlights the potential of Kv1.3 blockers as therapeutic agents for renal fibrosis and other M2 polarization-related diseases.

The activation of mast cells (MCs) and mediator release are closely related to the pathophysiology of irritable bowel syndrome (IBS). However, the exact underlying mechanisms are still not completely understood. The nuclear receptor subfamily 4a (Nr4a) is a family of orphan nuclear receptors implicated in regulating MC activation, degranulation, cytokine/chemokine synthesis and release. Acute and chronic stress trigger hypothalamic–pituitaryadrenal axis (HPA) activation to induce the release of corticotropin-releasing hormone (CRH), resulting in MC activation and induction of the Nr4a family. Our newest data showed that Nr4a members were specially over-expressed in colonic MCs of the chronic water-avoidance stress (WAS)-induced visceral hyperalgesia mice, suggesting that Nr4a members might be involved in the pathophysiology of visceral hypersensitivity. In this review, we highlight the present knowledge on roles of Nr4a members in the activation of MCs and the pathophysiology of IBS, and discuss signaling pathways that modulate the activation of Nr4a family members. We propose that a better understanding of Nr4a members and their modulators may facilitate the development of more selective and effective therapies to treat IBS patients.

Abstract Background Calcitonin gene-related peptide (CGRP) as a mediator of microglial activation at the transcriptional level may facilitate nociceptive signaling. Trimethylation of H3 lysine 27 (H3K27me3) by enhancer of zeste homolog 2 (EZH2) is an epigenetic mark that regulates inflammatory-related gene expression after peripheral nerve injury. In this study, we explored the relationship between CGRP and H3K27me3 in microglial activation after nerve injury, and elucidated the underlying mechanisms in the pathogenesis of chronic neuropathic pain. Methods Microglial cells (BV2) were treated with CGRP and differentially enrichments of H3K27me3 on gene promoters were examined using ChIP-seq. A chronic constriction injury (CCI) rat model was used to evaluate the role of CGRP on microglial activation and EZH2/H3K27me3 signaling in CCI-induced neuropathic pain. Results Overexpressions of EZH2 and H3K27me3 were confirmed in spinal microglia of CCI rats by immunofluorescence. CGRP treatment induced the increased of H3K27me3 expression in the spinal dorsal horn and cultured microglial cells (BV2) through EZH2. ChIP-seq data indicated that CGRP significantly altered H3K27me3 enrichments on gene promoters in microglia following CGRP treatment, including 173 gaining H3K27me3 and 75 losing this mark, which mostly enriched in regulation of cell growth, phagosome, and inflammation. qRT-PCR verified expressions of representative candidate genes (TRAF3IP2, BCL2L11, ITGAM, DAB2, NLRP12, WNT3, ADAM10) and real-time cell analysis (RTCA) verified microglial proliferation. Additionally, CGRP treatment and CCI increased expressions of ITGAM, ADAM10, MCP-1, and CX3CR1, key mediators of microglial activation in spinal dorsal horn and cultured microglial cells. Such increased effects induced by CCI were suppressed by CGRP antagonist and EZH2 inhibitor, which were concurrently associated with the attenuated mechanical and thermal hyperalgesia in CCI rats. Conclusion Our findings highly indicate that CGRP is implicated in the genesis of neuropathic pain through regulating microglial activation via EZH2-mediated H3K27me3 in the spinal dorsal horn.

Non-small-cell lung cancer (NSCLC) is one of the most common malignancies, and specific molecular targets are still lacking. Angiogenesis plays a central regulatory role in the growth and metastasis of malignant tumors and angiogenic factors (AFs) are involved. Although there are many studies comparing AFs and cancer, a prognostic risk model for AFs and cancer in humans has not been reported in the literature. This study aimed to identify the key AFs closely related to the process of NSCLC development, and four genes have been found, C1QTNF6, SLC2A1, PTX3, and FSTL3. Then, we constructed a novel prognostic risk model based on these four genes in non-small-cell lung cancer (NSCLC) and fully analyzed the relationship with clinical features, immune infiltration, genomes, and predictors. This model had good discrimination and calibration and will perform well in predicting the prognosis of treatment in clinical practice.